Excessive excitation by neurotransmitters can cause the degeneration and death of neurones. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA), glutamate and aspartate, at the N-methyl-D-aspartate (NMDA), the alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. This excitotoxic action is responsible for the loss of neurones in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from near-drowning, pulmonary surgery and cerebral trauma as well as lathyrism, Alzheimer""s, and Huntington""s diseases. Compounds capable of blocking excitatory amino acid receptors are therefore considered useful for the treatment of the above disorders and diseases, as well as Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain and drug addiction.
It is an object of the present invention to provide novel indole-2,3-dione-3-oxime derivatives which are excitatory amino acid antagonists and useful in the treatment of disorders or diseases of mammals, including humans, which are responsive to excitatory amino acid receptor antagonists.
Accordingly, in its first aspect, the invention provides the novel indole-2,3-dione-3-oxime derivatives described in claim 1.
In another aspect the invention relates to the use of a chemical compound of the invention for the preparation of a pharmaceutical composition.
In a third aspect the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the chemical compound of the invention together and a pharmaceutically acceptable excipient, carrier or diluent.
In a fourth aspect the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment of a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists.
In a more specific aspect the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment a cerebrovascular disorder, lathyrism, Alzheimer""s disease, Huntington""s diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
In a fifth aspect the invention provides a method of treating disorders or diseases of living animals, including humans, which are responsive to excitatory amino acid receptor antagonists, comprising administering to a living animal body, including a human, in need thereof an effective amount of a chemical compound of the invention.
In a more specific aspect the invention provides a method of treating a cerebrovascular disorder, lathyrism, Alzheimer""s disease, Huntington""s diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
In a sixth aspect the invention relates to the use of the chemical compound of the invention in a method of treating a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists, said method comprising administering to a living animal body, including a human, in need thereof an effective amount of the chemical compound.
In a more specific aspect the invention relates to the use of the chemical compound of the invention in a method of treating a cerebrovascular disorder, lathyrism, Alzheimer""s disease, Huntington""s diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
In a seventh aspect the invention provides a method of preparing a chemical compound of the invention.
Other objectives of the present invention will be apparent to the skilled person hereinafter.
Indole2,3-dione-3-oxime Derivatives
In its first aspect, the present invention provides novel indole-2,3-dione-3-oxime derivatives. The novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (I): 
wherein
R1 represents hydrogen, alkyl or benzyl;
R3 represents xe2x80x9cHetxe2x80x9d, or a group of the following formula 
xe2x80x83wherein
xe2x80x9cHetxe2x80x9d represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, which ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, alkoxy, and oxo; and
at least one of R31, R32, and R33 independently represents hydrogen, alkyl, or hydroxyalkyl, and
at least one of R31, R32, and R33 independently represents (CH2)nR34; wherein
R34 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, CONR35R36, or xe2x80x9cHetxe2x80x9d; wherein
R35 and R36 represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, aryl, aralkyl, or (CH2)nxe2x80x94R37; wherein
xe2x80x83R37 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxy-carbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; or
R35 and R36 together with the N-atom to which they are attached form a saturated 5- to 6-membered, heterocyclic ring, optionally containing one additional N or O atom; and
xe2x80x9cHetxe2x80x9d is as defined above; and
n is 0, 1, 2, or 3; and
R5 represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, NO2, amino, alkyl, alkoxy, phenyl and SO2NR51R52; wherein
R51 and R52 each independently represents hydrogen or alkyl; or
R51 and R52 together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom; and
xe2x80x9cAxe2x80x9d represents a ring of five to seven atoms fused with the benzo ring at the positions marked xe2x80x9caxe2x80x9d and xe2x80x9cbxe2x80x9d, and formed by the following bivalent radicals:
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b;
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b;
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b; or
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b; wherein
R6 represents hydrogen, alkyl or CH2CH2OH;
or a pharmaceutically acceptable salt thereof.
In a more preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula, (I), above, wherein xe2x80x9cHetxe2x80x9d is a lactone ring of the general formula (VI): 
and wherein m is 1, 2, 3 or 4; and
In another preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (II): 
wherein
R1 represents hydrogen, alkyl or benzyl;
xe2x80x9cHetxe2x80x9d represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, which ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, alkoxy, and oxo;
n is 0, 1, 2, or 3;
R5 represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, NO2, amino, alkyl, alkoxy, phenyl and SO2NR51R52; wherein
R51 and R52 each independently represents hydrogen or alkyl; or
R51 and R52 together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom; and
xe2x80x9cAxe2x80x9d represents a ring of five to seven atoms fused with the benzo ring at the positions marked xe2x80x9caxe2x80x9d and xe2x80x9cbxe2x80x9d, and formed by the following bivalent radicals:
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b;
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b;
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b; or
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b; wherein
R6 represents hydrogen, alkyl or CH2CH2OH.
In a more preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (II), above, wherein n is 0, 1 or 2; and
R5 represents phenyl or pyridyl, both of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, NO2, amino, alkyl, alkoxy, phenyl and SO2NR51R52; wherein
R51 and R52 each independently represents hydrogen or alkyl; or
R51 and R52 together with the N-atom to which they are attached form a chain xe2x80x94(CH2)mxe2x80x94,
wherein m is 2, 3, 4, 5 or 6.
In another preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (III): 
wherein
R1, R5, R6, xe2x80x9cHetxe2x80x9d, and n are as defined above.
In a yet more embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (II), wherein
xe2x80x9cHetxe2x80x9d is a lactone of the general formula (VII): 
wherein p is 1, 2, 3, or 4.
In another preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (IV): 
wherein
R1 represents hydrogen, alkyl or benzyl;
at least one of R31, R32, and R33 independently represents hydrogen, alkyl, or hydroxyalkyl, and
at least one of R31, R32, and R33 independently represents (CH2)nR34; wherein
R34 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, or CONR35R36; wherein
R35 and R36 represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, aryl, aralkyl, or (CH2)nxe2x80x94R37; wherein
R37 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxy-carbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; or
R35 and R36 together with the N-atom to which they are attached form a saturated 5- to 6-membered, heterocyclic ring, optionally containing one additional N or O atom; and
n is 0, 1, 2, or 3; or
one of R31, R32, and R33 represents hydrogen or alkyl, and two of R31, R32, and R33 together form a lactone ring of the general formula (VI): 
wherein m is 1, 2 or 3; and
R5 represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, NO2, amino, alkyl alkoxy, phenyl and SO2NR51R52; wherein
R51 and R52 each independently represents hydrogen or alkyl; or
R51 and R52 together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom; and
xe2x80x9cAxe2x80x9d represents a ring of five to seven atoms fused with the benzo ring at the positions marked xe2x80x9caxe2x80x9d and xe2x80x9cbxe2x80x9d, and formed by the following bivalent radicals:
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b;
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b;
axe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94CH2xe2x80x94b;
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94CH2xe2x80x94b; or
axe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NR6xe2x80x94b; wherein
R6 represents hydrogen, alkyl or CH2CH2OH;
or a pharmaceutically acceptable salt thereof.
In a more preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (V): 
wherein R1, R31, R32, R33, R5, and R6 are as defined under formula (IV) above.
Definition of Substituents
In the context of this invention alkyl designates a straight chain or a branched chain containing of from one to six carbon atoms (C1-C6 alkyl), including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. In a preferred embodiment of this invention alkyl represents a C1-C4 alkyl, preferably a C1-C3 alkyl, most preferred methyl, ethyl, propyl or isopropyl.
In the context of this invention cycloalkyl designates a cyclic alkyl containing of from three to seven carbon atoms (C3-C7 cycloalkyl), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
In the context of this invention alkenyl designates a group containing of from two to six carbon atoms (C2-C6 alkenyl), including at least one double bond, for example, but not limited to ethenyl, 1,2- or 2,3-propenyl, 1,2-, 2,3-, or 3,4-butenyl.
In the context of this invention alkynyl designates a group containing of from two to six carbon atoms (C2-C6 alkynyl), including at least one triple bond, for example, but not limited to ethynyl, 1,2- or 2,3-propynyl, 1,2-, 2,3- or 3,4-butynyl.
In the context of this invention cycloalkyl-alkyl designates a cycloalkyl as defined above which is attached to an alkyl as also defined above, e.g. cyclopropylmethyl.
In the context of this invention aryl designates an aromatic hydrocarbon, such as phenyl or naphthyl.
In the context of this invention aralkyl designates an aryl as defined above which is attached to an alkyl as also defined above, e.g. benzyl.
In the context of this invention alkoxy designates an alkyl-Oxe2x80x94 where alkyl is as defined above.
In the context of this invention alkoxycarbonyl designates an alkyl-Oxe2x80x94COxe2x80x94 where alkyl is as defined above.
In the context of this invention cycloalkoxycarbonyl designates a cycloalkyl-Oxe2x80x94COxe2x80x94 where cycloalkyl is as defined above.
In the context of this invention cycloalkyl-alkoxycarbonyl designates a cycloalkyl-alkylxe2x80x94Oxe2x80x94COxe2x80x94 where cycloalkyl-alkyl is as defined above.
In the context of this invention alkenyloxycarbonyl designates an alkenyl-Oxe2x80x94COxe2x80x94 where alkenyl is as defined above.
In the context of this invention alkynyloxycarbonyl designates an alkynyl-Oxe2x80x94COxe2x80x94 where alkynyl is as defined above.
In the context of this invention aryloxycarbonyl designates an aryl-Oxe2x80x94COxe2x80x94 where aryl is as defined above.
In the context of this invention aralkoxycarbonyl designates an aralkyl-Oxe2x80x94COxe2x80x94 where aralkyl is as defined above.
In the context of this invention halogen represents fluorine, chlorine, bromine and iodine.
In the context of this invention amino represents NH2, NH-alkyl, or N-(alkyl)2, wherein alkyl is as defined above.
In a more specific aspect, the novel indole-2,3-dione-3-oxime derivatives of the invention is
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(3-(2-oxo)tetrahydrofuryl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(5-(4-bromo-3-methoxy)isoxazolylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(5-(4-bromo-3-ethoxy)isoxazolylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-8-7-9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(4-(N,5dimethyl-3-oxo)isoxazolylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(4-(N-methyl-5-tertbutyl-3-oxo)isoxazolylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(4-(5-methyl-3-methoxy)isoxazolylmethyl)oxime; or
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(4-(5methyl-3-ethoxy)isoxazolylmethyl)oxime;
or a pharmaceutically acceptable salt hereof.
In another specific embodiment, the novel indole-2,3-dione-3-oxime derivatives of the invention is
1-methyl-8-methyl-5-phenyl-6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(carboxymethyl)oxime;
1-methyl-8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl)oxime;
1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(carboxymethyl)oxime;
1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(1-ethoxycarbonyl-1-methylethyl)oxime;
1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(carboxymethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(1-carboxy-1-methylethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(isopropoxycarbonylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(1-ethoxycarbonyl-1-methyl)ethyloxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(t-butoxycarbonylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(N,N-dimethylcarbamoylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(N-methylcarbamoylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(N-phenylcarbamoylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(N,N-di(2-hydroxyethyl)carbamoylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione3-O-(morpholinocarbonylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethylcarbamoylmethyl)oxime;
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(N,N-di(2-(N,N-diethylamino)ethyl)carbamoyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(carboxymethyl)oxime;
8-methyl-5-(4-(N,N-imethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(2-hydroxyethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(1-carboxy-1-methylethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsultamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(cyclopropylmethoxycarbonylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(isopropoxycarbonylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(N,N-dimethyl-carbamoylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(piperidinocarbonylmethyl)oxime;
8-methyl-5-(4-(piperidinosulfonyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(piperidinocarbonylmethyl)oxime;
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(morpholinocarbonylmethyl)oxime; or
8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime;
or a pharmaceutically acceptable salt hereof.
Steric Isomers
Some of the chemical compounds of the present invention exist in (+) and (xe2x88x92) forms as well as in racemic forms.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof, with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or l-(tartrates, mandelates, or camphorsulphonate) salts for example.
The chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (xe2x88x92) phenylalanine, (+) or (xe2x88x92) phenylglycine, (+) or (xe2x88x92) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J, Colet A, and Wilen S in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Moreover, being oximes, the chemical compounds of the invention may exist in two forms, syn- and anti-form, depending on the arrangement of the substituents around the xe2x80x94Cxe2x95x90Nxe2x80x94 double bond. A chemical compound of the present invention may thus be the syn- or the anti-form, or it may be a mixture hereof.
Pharmaceutically Acceptable Salts
The novel indole-2,3-dione-3-oxime derivatives of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate, stearate, succinate, glutamate, glycollate, toluene-p-sulphonate, formate, malonate, naphthalene-2-sulphonate, salicylate and the acetate. Such salts are formed by procedures well known in the art.
Other acids such as oxalic acid, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt, of a chemical compound of the invention containing a carboxy group.
The chemical compound of the invention may be provided in solved or dissolved form together with a pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solved forms are considered equivalent to dissolved forms for the purposes of this invention.
Pharmaceutical Compositions
In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention. While a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or more excipients, carriers and/or diluents.
In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation.
The chemical compound of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Compositions containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The chemical compound of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
For preparing pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
The chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take""such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
For topical administration to the epidermis the chemical compound according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by Means of an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Biological Activity and Methods of Treatment
The novel indole-2,3-dione-3-oxime derivatives and the pharmaceutically acceptable salts of the invention possess valuable therapeutic properties. In particular the novel indole-2,3-dione-3-oxime derivatives of the invention are excitatory amino acid antagonists and useful in the treatment of disorders or diseases of mammals, including humans, which are responsive to excitatory amino acid receptor antagonists. The same biological activity applies to physiologic metabolites of the novel indole-2,3-dione-3-oxime derivatives of the invention.
The chemical compound of this invention is useful in the treatment of central nervous system disorders related to their biological activity. More particularly the novel indole-2,3-dione-3-oxime derivatives of the invention show strong excitatory amino acid (EAA) antagonising properties at the AMPA ((RS)-alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding site.
The chemical compound of this invention may accordingly be administered to a subject, including a human, in need of treatment, alleviation, or elimination of a disorder or disease associated with the biological activity of the compound. This includes especially cerebral ischaemia, cerebral infarction, excitatory amino acid dependent, including glutamate and/or aspartate dependent Lathyrism, Alzheimer""s and Huntington""s diseases, Amyotropic Lateral sclerosis, psychosis, Parkinsonism, epilepsy, anxiety, pain (migraine), drug addiction and convulsions.
Therefore the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment of a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists.
In a more specific aspect the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment a cerebrovascular disorder, lathyrism, Alzheimer""s disease, Huntington""s diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
Also, the invention provides a method of treating disorders or diseases of living animals, including humans, which are responsive to excitatory amino acid receptor antagonists, comprising administering to a living animal body, including a human, in need thereof an effective amount of a chemical compound of the invention.
In a more specific aspect the invention provides a method of treating a cerebrovascular disorder, lathyrism, Alzheimer""s disease, Huntington""s diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
Suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
Methods of Preparation
The novel indole-2,3-dione-3-oxime derivatives of the invention may be prepared by conventional methods of chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
The end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
In yet another aspect the invention provides a method of preparing a chemical compound of the invention which comprises the step of reacting a compound having the general formula 
wherein R1, R5, and xe2x80x9cAxe2x80x9d have the meanings set forth above, with a compound having the formula 
wherein R3 and m have the meanings set forth above, optionally followed by converting the thus obtained compound to another compound of the invention or to a pharmaceutically acceptable salt hereof by using conventional methods.